{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:27:45Z","timestamp":1790972865359,"version":"4.1.0"},"reference-count":116,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Thoracic aortic aneurysm and dissection (TAAD) encompasses a clinically heterogeneous group of diseases characterized by high morbidity and mortality. Genetic studies over the past two decades have significantly expanded our understanding of the molecular landscape underlying heritable TAAD, revealing contributions from multiple interconnected biological pathways. This review systematically summarizes more than 75 genes implicated in TAAD pathogenesis, categorizing them according to major mechanistic roles including TGF-\u03b2 signaling, extracellular matrix remodeling, smooth muscle cell contractility and cytoskeletal regulation, cell\u2013matrix and cell\u2013cell adhesion, metabolic processes, ion transport, and transcriptional regulation. Special emphasis is placed on emerging genes with variable or overlapping clinical phenotypes, dual-mechanism candidates, and their implications for personalized clinical management, including surveillance and surgical intervention thresholds. The integration of molecular insights into clinical practice, along with cautious consideration of genes of uncertain significance, promises to enhance diagnostic precision and risk stratification in individuals and families affected by heritable aortic disease.<\/jats:p>","DOI":"10.3390\/medsci13030155","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T06:25:57Z","timestamp":1756189557000},"page":"155","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Expanding Genetic Architecture of Arteriopathies: From Canonical TAAD Genes to Emerging Connective Tissue and Signaling Pathways"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5144-9292","authenticated-orcid":false,"given":"Luke","family":"Dreher","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Mayo Clinic Arizona, 5777 East Mayo Blvd, Phoenix, AZ 85054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0940-0168","authenticated-orcid":false,"given":"Hussein","family":"Abdul Nabi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Mayo Clinic Arizona, 5777 East Mayo Blvd, Phoenix, AZ 85054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4302-5729","authenticated-orcid":false,"given":"Hunter","family":"Vandolah","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Mayo Clinic Arizona, 5777 East Mayo Blvd, Phoenix, AZ 85054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3224-1621","authenticated-orcid":false,"given":"Stephen","family":"Brennan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Galway, H91 TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9296-2824","authenticated-orcid":false,"given":"George","family":"Bcharah","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Mayo Clinic Arizona, 5777 East Mayo Blvd, Phoenix, AZ 85054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hend","family":"Bcharah","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Mayo Clinic Arizona, 5777 East Mayo Blvd, Phoenix, AZ 85054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayowa A.","family":"Osundiji","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic Arizona, Phoenix, AZ 85054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4230-5032","authenticated-orcid":false,"given":"Linnea M.","family":"Baudhuin","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadi E.","family":"Shamoun","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Mayo Clinic Arizona, 5777 East Mayo Blvd, Phoenix, AZ 85054, USA"},{"name":"Department of Clinical Genomics, Mayo Clinic Arizona, Phoenix, AZ 85054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1161\/01.CIR.0000154569.08857.7A","article-title":"Thoracic and abdominal aortic aneurysms","volume":"111","author":"Isselbacher","year":"2005","journal-title":"Circulation"},{"key":"ref_2","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (2025, July 02). Heritable Thoracic Aortic Disease Overview, GeneReviews, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1120\/."},{"key":"ref_3","unstructured":"Dreher, L. (2025, July 02). TAAD Pathway Integration Network. Available online: https:\/\/BioRender.com\/owqlfp6."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/s41588-023-01420-z","article-title":"Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program","volume":"55","author":"Klarin","year":"2023","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e033232","DOI":"10.1161\/JAHA.123.033232","article-title":"Contributions of Germline and Somatic Mosaic Genetics to Thoracic Aortic Aneurysms in Nonsyndromic Individuals","volume":"13","author":"Chen","year":"2024","journal-title":"J. Am. Heart Assoc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"147727","DOI":"10.1016\/j.gene.2023.147727","article-title":"Genetic architecture of thoracic aortic dissection in the female population","volume":"887","author":"Chen","year":"2023","journal-title":"Gene"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Magouliotis, D.E., Sicouri, S., Sicouri, N., Baudo, M., Cabrucci, F., Yamashita, Y., and Ramlawi, B. (2025). Epigenetic Biomarkers in Thoracic Aortic Aneurysm, Dissection, and Bicuspid Aortopathy: A Comprehensive Review. Biomolecules, 15.","DOI":"10.3390\/biom15040568"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.jjcc.2019.03.014","article-title":"Genetic basis of hereditary thoracic aortic aneurysms and dissections","volume":"74","author":"Takeda","year":"2019","journal-title":"J. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev-genom-111521-104455","article-title":"The Genetics and Typical Traits of Thoracic Aortic Aneurysm and Dissection","volume":"23","author":"Meester","year":"2022","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ostberg, N.P., Zafar, M.A., Ziganshin, B.A., and Elefteriades, J.A. (2020). The Genetics of Thoracic Aortic Aneurysms and Dissection: A Clinical Perspective. Biomolecules, 10.","DOI":"10.3390\/biom10020182"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/gim.2014.11","article-title":"Loeys-Dietz syndrome: A primer for diagnosis and management","volume":"16","author":"MacCarrick","year":"2014","journal-title":"Genet. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/ng1511","article-title":"A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2","volume":"37","author":"Loeys","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/ng.744","article-title":"Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis","volume":"43","author":"Oldenburg","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajmg.c.31552","article-title":"The 2017 international classification of the Ehlers-Danlos syndromes","volume":"175","author":"Malfait","year":"2017","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1002\/ajmg.c.32038","article-title":"COL1A1 and COL1A2 variants in Ehlers-Danlos syndrome phenotypes and COL1-related overlap disorder","volume":"193","author":"Venable","year":"2023","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_16","first-page":"101193","article-title":"FBN2 pathogenic mutation in congenital contractural arachnodactyly with severe skeletal manifestations","volume":"42","author":"Huang","year":"2025","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1086\/425231","article-title":"ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome","volume":"75","author":"Dagoneau","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1086\/504304","article-title":"Fibulin-4: A novel gene for an autosomal recessive cutis laxa syndrome","volume":"78","author":"Hucthagowder","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e334","DOI":"10.1161\/CIR.0000000000001106","article-title":"2022 ACC\/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association\/American College of Cardiology Joint Committee on Clinical Practice Guidelines","volume":"146","author":"Isselbacher","year":"2022","journal-title":"Circulation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1055\/s-0039-3400233","article-title":"Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2019 Update and Clinical Implications","volume":"7","author":"Brownstein","year":"2019","journal-title":"Aorta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.matbio.2018.04.005","article-title":"Genetics of the extracellular matrix in aortic aneurysmal diseases","volume":"71\u201372","author":"Lin","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Moitra, K., Garcia, S., Jaldin, M., Etoundi, C., Cooper, D., Roland, A., Dixon, P., Reyes, S., Turan, S., and Terry, S. (2017). ABCC6 and Pseudoxanthoma Elasticum: The Face of a Rare Disease from Genetics to Advocacy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071488"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.jacc.2018.04.089","article-title":"Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection","volume":"72","author":"Renard","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_24","unstructured":"(2025, June 16). Online Mendelian Inheritance in Man (OMIM), Available online: https:\/\/www.ncbi.nlm.nih.gov\/omim."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.ajhg.2009.04.007","article-title":"Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease","volume":"84","author":"Guo","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wei, X., Sun, Y., Wu, Y., Zhu, J., Gao, B., Yan, H., Zhao, Z., Zhou, J., and Jing, Z. (2017). Downregulation of Talin-1 expression associates with increased proliferation and migration of vascular smooth muscle cells in aortic dissection. BMC Cardiovasc Disord, 17.","DOI":"10.1186\/s12872-017-0588-0"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/bs.apha.2022.02.002","article-title":"Beyond hypertension: Diastolic dysfunction associated with cancer treatment in the era of cardio-oncology","volume":"94","author":"Minotti","year":"2022","journal-title":"Adv. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.ajhg.2016.12.010","article-title":"Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa","volume":"100","author":"Gardeitchik","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1161\/ATVBAHA.119.313374","article-title":"Copper Transporter ATP7A (Copper-Transporting P-Type ATPase\/Menkes ATPase) Limits Vascular Inflammation and Aortic Aneurysm Development: Role of MicroRNA-125b","volume":"39","author":"Sudhahar","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.ajhg.2013.04.003","article-title":"Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders","volume":"92","author":"Nakajima","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s13023-017-0704-3","article-title":"Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome","volume":"12","author":"Ritelli","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/gim.2016.126","article-title":"Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections","volume":"19","author":"Meester","year":"2017","journal-title":"Genet. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1475-2891-14-6","article-title":"Role of homocysteine in the development of cardiovascular disease","volume":"14","author":"Ganguly","year":"2015","journal-title":"Nutr. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e001605","DOI":"10.1161\/CIRCGENETICS.116.001605","article-title":"Identification of Cadherin 2 (CDH2) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy","volume":"10","author":"Mayosi","year":"2017","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/ajmg.a.37383","article-title":"The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations","volume":"170A","author":"Janecke","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.biocel.2014.04.020","article-title":"Collagen XII: Protecting bone and muscle integrity by organizing collagen fibrils","volume":"53","author":"Chiquet","year":"2014","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"53331","DOI":"10.1074\/jbc.M409622200","article-title":"Type V collagen controls the initiation of collagen fibril assembly","volume":"279","author":"Wenstrup","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1128\/MCB.02085-07","article-title":"Core glycosylation of collagen is initiated by two beta(1-O)galactosyltransferases","volume":"29","author":"Schegg","year":"2009","journal-title":"Mol. Cell Biol."},{"key":"ref_39","first-page":"639","article-title":"Activation of Wnt\/\u03b2-catenin signaling in abdominal aortic aneurysm: A potential therapeutic opportunity?","volume":"10","author":"Varona","year":"2022","journal-title":"Genes Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"w13553","DOI":"10.4414\/smw.2012.13553","article-title":"Risky communication in atherosclerosis and thrombus formation","volume":"142","author":"Meens","year":"2012","journal-title":"Swiss Med. Wkly."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Shen, Y., Russo, V., Zeglinski, M.R., Sellers, S.L., Wu, Z., Oram, C., Santacruz, S., Merkulova, Y., Turner, C., and Tauh, K. (2017). Recombinant Decorin Fusion Protein Attenuates Murine Abdominal Aortic Aneurysm Formation and Rupture. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-16194-8"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103798","DOI":"10.1016\/j.ejmg.2019.103798","article-title":"DSE associated musculocontractural EDS, a milder phenotype or phenotypic variability","volume":"63","author":"Schirwani","year":"2020","journal-title":"Eur. J. Med. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Brand\u00e3o, M., Bariani, R., Rigato, I., and Bauce, B. (2023). Desmoplakin Cardiomyopathy: Comprehensive Review of an Increasingly Recognized Entity. J. Clin. Med., 12.","DOI":"10.3390\/jcm12072660"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e002971","DOI":"10.1161\/CIRCGEN.120.002971","article-title":"Genetic Diagnosis and the Severity of Cardiovascular Phenotype in Patients With Elastin Arteriopathy","volume":"13","author":"Min","year":"2020","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1242\/dmm.015255","article-title":"TGF-\u03b2 mediates early angiogenesis and latent fibrosis in an Emilin1-deficient mouse model of aortic valve disease","volume":"7","author":"Munjal","year":"2014","journal-title":"Dis. Model. Mech."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1146\/annurev-pathmechdis-051222-121126","article-title":"ENPP1 in Blood and Bone: Skeletal and Soft Tissue Diseases Induced by ENPP1 Deficiency","volume":"19","author":"Ferreira","year":"2024","journal-title":"Annu. Rev. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.matbio.2014.02.004","article-title":"Fibulin-4 and fibulin-5 in elastogenesis and beyond: Insights from mouse and human studies","volume":"37","author":"Papke","year":"2014","journal-title":"Matrix Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1111\/cge.12702","article-title":"Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections","volume":"89","author":"Regalado","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/ajmg.a.38580","article-title":"Thoracic aortic aneurysm in patients with loss of function Filamin A mutations: Clinical characterization, genetics, and recommendations","volume":"176","author":"Chen","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.4103\/0366-6999.189902","article-title":"A Novel Mutation of Filamin A Gene in a Chinese Family with Periventricular Nodular Heterotopia","volume":"129","author":"Zhou","year":"2016","journal-title":"Chin. Med. J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1007\/s10741-021-10172-z","article-title":"Filamin C in cardiomyopathy: From physiological roles to DNA variants","volume":"27","author":"Song","year":"2022","journal-title":"Heart Fail. Rev."},{"key":"ref_52","first-page":"1259","article-title":"A novel GJA5 variant associated with increased risk of essential hypertension","volume":"15","author":"Wang","year":"2023","journal-title":"Am. J. Transl. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/s41436-020-00939-4","article-title":"Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms","volume":"23","author":"Dombrowsky","year":"2021","journal-title":"Genet. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1002\/bies.20048","article-title":"hnRNP K: One protein multiple processes","volume":"26","author":"Bomsztyk","year":"2004","journal-title":"Bioessays"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1017\/S1355838202024627","article-title":"The poly(C)-binding proteins: A multiplicity of functions and a search for mechanisms","volume":"8","author":"Makeyev","year":"2002","journal-title":"RNA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.ajhg.2021.04.019","article-title":"A human importin-\u03b2-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8","volume":"108","author":"Meester","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/j.ajhg.2021.04.020","article-title":"Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation","volume":"108","author":"Ziegler","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1002\/humu.24433","article-title":"Isolated aneurysmal disease as an underestimated finding in individuals with JAG1 pathogenic variants","volume":"43","author":"Votypka","year":"2022","journal-title":"Hum. Mutat."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/j.2040-4603.2017.tb00747.x","article-title":"Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles","volume":"7","author":"Tykocki","year":"2017","journal-title":"Compr. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Crasto, S., My, I., and Di Pasquale, E. (2020). The Broad Spectrum of LMNA Cardiac Diseases: From Molecular Mechanisms to Clinical Phenotype. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00761"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1055\/s-0038-1639612","article-title":"Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2018 Update and Clinical Implications","volume":"6","author":"Brownstein","year":"2018","journal-title":"Aorta"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s00395-024-01053-1","article-title":"Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections","volume":"119","author":"Ganizada","year":"2024","journal-title":"Basic. Res. Cardiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/dvdy.331","article-title":"The role of LTBPs in TGF beta signaling","volume":"251","author":"Rifkin","year":"2022","journal-title":"Dev. Dyn."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Chen, S.W., Chou, S.H., Tung, Y.C., Hsiao, F.C., Ho, C.T., Chan, Y.H., Wu, V.C., Chou, A.H., Hsu, M.E., and Lin, P.J. (2021). Expression and role of lumican in acute aortic dissection: A human and mouse study. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0255238"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ajhg.2014.11.015","article-title":"MAT2A mutations predispose individuals to thoracic aortic aneurysms","volume":"96","author":"Guo","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Zha, L., Wu, J., Wang, M., Zhou, M., Wu, G., Cheng, X., Huang, Z., Xie, Q., and Tu, X. (2022). MED12 Regulates Smooth Muscle Cell Functions and Participates in the Development of Aortic Dissection. Genes., 13.","DOI":"10.3390\/genes13040692"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ijcard.2022.07.008","article-title":"Microfiber-associated protein 5 (MFAP5): A promising approach to discover new biomarkers for heart failure and cardiac remodeling","volume":"366","author":"Cheng","year":"2022","journal-title":"Int. J. Cardiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/ng1721","article-title":"Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm\/aortic dissection and patent ductus arteriosus","volume":"38","author":"Zhu","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.ijcard.2011.08.079","article-title":"Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGF\u03b2 signaling in FTAAD","volume":"165","author":"Renard","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e13697","DOI":"10.1111\/eci.13697","article-title":"The role of vascular smooth muscle cells in the development of aortic aneurysms and dissections","volume":"52","author":"Rombouts","year":"2022","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1161\/CIRCGENETICS.110.959171","article-title":"Gene mutations and familial thoracic aortic aneurysms: A walk on the mild side","volume":"4","author":"Spin","year":"2011","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0070-2153(10)92011-5","article-title":"Notch signaling in cardiac development and disease","volume":"92","author":"MacGrogan","year":"2010","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/nature03940","article-title":"Mutations in NOTCH1 cause aortic valve disease","volume":"437","author":"Garg","year":"2005","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"7054","DOI":"10.1111\/jcmm.14607","article-title":"Novel polymorphisms in PDLIM3 and PDLIM5 gene encoding Z-line proteins increase risk of idiopathic dilated cardiomyopathy","volume":"23","author":"Wang","year":"2019","journal-title":"J. Cell Mol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1161\/CIRCULATIONAHA.105.568642","article-title":"Clinical features of arrhythmogenic right ventricular dysplasia\/cardiomyopathy associated with mutations in plakophilin-2","volume":"113","author":"Dalal","year":"2006","journal-title":"Circulation"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1136\/jmedgenet-2019-106019","article-title":"Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications","volume":"56","author":"Ewans","year":"2019","journal-title":"J. Med. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Sharad, S., Dobi, A., Srivastava, S., Srinivasan, A., and Li, H. (2020). PMEPA1 Gene Isoforms: A Potential Biomarker and Therapeutic Target in Prostate Cancer. Biomolecules, 10.","DOI":"10.3390\/biom10091221"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Moore, P., Wolf, A., and Sathyamoorthy, M. (2024). An Eye into the Aorta: The Role of Extracellular Matrix Regulatory Genes ZNF469 and PRDM5, from Their Previous Association with Brittle Cornea Syndrome to Their Novel Association with Aortic and Arterial Aneurysmal Diseases. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115848"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.ajhg.2013.06.019","article-title":"Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections","volume":"93","author":"Guo","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/nm1742","article-title":"Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability","volume":"14","author":"Jones","year":"2008","journal-title":"Nat. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e93187","DOI":"10.1172\/jci.insight.93187","article-title":"Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction","volume":"2","author":"Shimizu","year":"2017","journal-title":"JCI Insight"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"7994","DOI":"10.1038\/s41467-023-43851-6","article-title":"Selenoprotein deficiency disorder predisposes to aortic aneurysm formation","volume":"14","author":"Schoenmakers","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1038\/ng.2421","article-title":"Mutations in the TGF-\u03b2 repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm","volume":"44","author":"Doyle","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/ng1764","article-title":"Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome","volume":"38","author":"Coucke","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.celrep.2013.01.009","article-title":"ZIP8 regulates host defense through zinc-mediated inhibition of NF-\u03baB","volume":"3","author":"Liu","year":"2013","journal-title":"Cell Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e620","DOI":"10.1002\/mgg3.620","article-title":"A novel SMAD6 variant in a patient with severely calcified bicuspid aortic valve and thoracic aortic aneurysm","volume":"7","author":"Park","year":"2019","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1161\/CIRCULATIONAHA.121.057001","article-title":"SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension","volume":"145","author":"Veith","year":"2022","journal-title":"Circulation"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Li, Y.J., Zou, S., Bian, Y.Z., Liu, X.Y., Yang, C.X., Li, L., Qiu, X.B., Xu, Y.J., Yang, Y.Q., and Huang, R.T. (2025). Chromosomal Location and Identification of TBX20 as a New Gene Responsible for Familial Bicuspid Aortic Valve. Diagnostics, 15.","DOI":"10.20944\/preprints202502.1131.v1"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Matsumoto, K.I., and Aoki, H. (2020). The Roles of Tenascins in Cardiovascular, Inflammatory, and Heritable Connective Tissue Diseases. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.609752"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/ng.2348","article-title":"TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome","volume":"44","author":"Boileau","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1016\/j.jacc.2015.01.040","article-title":"Mutations in a TGF-\u03b2 ligand, TGFB3, cause syndromic aortic aneurysms and dissections","volume":"65","author":"Gillis","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1091\/mbc.11.10.3353","article-title":"Matricellular proteins as modulators of cell-matrix interactions: Adhesive defect in thrombospondin 2-null fibroblasts is a consequence of increased levels of matrix metalloproteinase-2","volume":"11","author":"Yang","year":"2000","journal-title":"Mol. Biol. Cell"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/s41436-020-00947-4","article-title":"Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm","volume":"23","author":"Elbitar","year":"2021","journal-title":"Genet. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1161\/CIRCRESAHA.115.307130","article-title":"LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections","volume":"118","author":"Guo","year":"2016","journal-title":"Circ. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e002437","DOI":"10.1161\/CIRCGEN.118.002437","article-title":"Rare Missense Variants in TLN1 Are Associated With Familial and Sporadic Spontaneous Coronary Artery Dissection","volume":"12","author":"Turley","year":"2019","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Wang, H.Q., Yang, H., Tang, Q., Gong, Y.C., Fu, Y.H., Wan, F., Yang, B., Guo, R., Zhong, Y.L., and Zhu, J.M. (2020). Identification of Vinculin as a Potential Diagnostic Biomarker for Acute Aortic Dissection Using Label-Free Proteomics. Biomed. Res. Int., 2020.","DOI":"10.1155\/2020\/7806409"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Jones, K.A., Luo, Y., Dukes-Rimsky, L., Srivastava, D.P., Koul-Tewari, R., Russell, T.A., Shapiro, L.P., Srivastava, A.K., and Penzes, P. (2018). Neurodevelopmental disorder-associated ZBTB20 gene variants affect dendritic and synaptic structure. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203760"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.ajhg.2024.01.013","article-title":"Haploinsufficiency of ZFHX3, encoding a key player in neuronal development, causes syndromic intellectual disability","volume":"111","author":"Jacobs","year":"2024","journal-title":"Am. J. Hum. Genet."},{"key":"ref_99","unstructured":"Dreher, L. (2025, June 05). Central Illustration: Integrated Molecular Pathway Underlying Thoracic Aortic Aneurysm and Dissection. Available online: https:\/\/BioRender.com\/1hkoar3."},{"key":"ref_100","unstructured":"Dreher, L. (2025, June 05). Legend. Available online: https:\/\/BioRender.com\/ua3tzq9."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/ng1097-218","article-title":"Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome","volume":"17","author":"Pereira","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"eadg6298","DOI":"10.1126\/scitranslmed.adg6298","article-title":"Bioengineered vascular grafts with a pathogenic TGFBR1 variant model aneurysm formation in vivo and reveal underlying collagen defects","volume":"16","author":"Yang","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.hrcr.2019.10.001","article-title":"ACTN2 variant associated with a cardiac phenotype suggestive of left-dominant arrhythmogenic cardiomyopathy","volume":"6","author":"Good","year":"2019","journal-title":"HeartRhythm Case Rep."},{"key":"ref_104","unstructured":"Dreher, L. (2025, July 01). Functional Overlap of Genes Implicated in Heritable TAAD. Available online: https:\/\/BioRender.com\/jwulob5."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12931-017-0544-7","article-title":"The roles and regulation of the actin cytoskeleton, intermediate filaments and microtubules in smooth muscle cell migration","volume":"18","author":"Tang","year":"2017","journal-title":"Respir. Res."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Ritelli, M., Cinquina, V., Giacopuzzi, E., Venturini, M., Chiarelli, N., and Colombi, M. (2019). Further Defining the Phenotypic Spectrum of B3GAT3 Mutations and Literature Review on Linkeropathy Syndromes. Genes, 10.","DOI":"10.3390\/genes10090631"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1038\/s41388-019-1050-9","article-title":"PMEPA1 isoform a drives progression of glioblastoma by promoting protein degradation of the Hippo pathway kinase LATS1","volume":"39","author":"Ji","year":"2020","journal-title":"Oncogene"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"219","DOI":"10.7150\/jca.79236","article-title":"The Role of CTNNA1 in Malignancies: An Updated Review","volume":"14","author":"Huang","year":"2023","journal-title":"J. Cancer"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.1093\/eurheartj\/eht334","article-title":"Losartan reduces aortic dilatation rate in adults with Marfan syndrome: A randomized controlled trial","volume":"34","author":"Groenink","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"e009302","DOI":"10.1161\/JAHA.118.009302","article-title":"Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease","volume":"7","author":"Mariscalco","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1097\/HCO.0000000000000797","article-title":"Current management of the vascular subtype of Ehlers-Danlos syndrome","volume":"35","author":"Benrashid","year":"2020","journal-title":"Curr. Opin. Cardiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1126\/science.1124287","article-title":"Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome","volume":"312","author":"Habashi","year":"2006","journal-title":"Science"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e284","DOI":"10.1097\/MJT.0000000000000916","article-title":"New Directions in the Management of Peripheral Artery Disease","volume":"26","author":"Chioncel","year":"2019","journal-title":"Am. J. Ther."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1093\/ehjci\/jew292","article-title":"Hypertrophic cardiomyopathy with aortic dilation: A novel observation","volume":"18","author":"Yousefzai","year":"2017","journal-title":"Eur. Heart J. Cardiovasc. Imaging"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.echo.2020.11.003","article-title":"Prevalence and Clinical Correlates of Aortic Dilation in Hypertrophic Cardiomyopathy","volume":"34","author":"Geske","year":"2021","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ijcard.2021.10.013","article-title":"Sport practice in hypertrophic cardiomyopathy: Running to stand still?","volume":"345","author":"Mascia","year":"2021","journal-title":"Int. J. Cardiol."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/13\/3\/155\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:32:33Z","timestamp":1760034753000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/13\/3\/155"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,25]]},"references-count":116,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["medsci13030155"],"URL":"https:\/\/doi.org\/10.3390\/medsci13030155","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,25]]}}}